Acoustic overstimulation or hypertension modulates cochlear blood flow, causing temporary and reversible microischemia in the stria vascularis. Strial microischemia is characterized by irregularity in vessel diameters and elevated permeability, i.e. strial micro-leakage. Cochlear ischemia alone may cause abrupt hearing loss and tinnitus. Combined strial micro-leakage and systemic administration of aminoglycoside antibiotics can escalate aminoglycoside strial trafficking, and presumptively its ototoxicity. In this proposal, we will determine which risk factors, including sound exposure, hypertension or age can induce strial micro-leakage, and establish a reliable ototoxic mouse model. The specific aims of this project are to: Aim 1: validate a noise-induced strial micro-leakage mouse model. We will determine the acoustic stimulation conditions that reliably induce strial micro-leakage (e.g., single dose, interrupted sound exposures). Aim 2: determine the effect of hypertension or age in inducing strial micro-leakage, by increasing blood volume in CBA/CaJ mice. In addition, we will examine effect of age on strial micro-leakage in C57BL/6 mice, a strain with early onset of age-related hearing loss. Aim 3: determine if vasoactive reagents prevent strial micro-leakage. We will use vasodilators or vasoconstrictors to regulate the strial blood flow and determine if they reduce micro-leakage. The outcome of this project will establish a reliable mouse model for strial micro-leakage. This is important as microischemia may underlie several factors that increase the risk of ototoxicity, such as hypertension or poor blood flow. In addition, we seek to identify potential interventions to pharmacologically minimize strial microischemia, and reduce the risk of ototoxicity. PUBLIC HEALTH RELEVANCE: Acoustic overstimulation or hypertension modulates cochlear blood flow, causing temporary and reversible microischemia in the stria vascularis. Combination of cochlear microischemia and systemic administration of aminoglycoside antibiotics can escalate aminoglycoside intra-strial trafficking, and consequently its ototoxicity. The proposed research will determine several risk factors on strial microischemia, and establish a reliable ototoxic mouse model.